The invention relates in general to nucleic acids and more particularly to the use of genes differentially expressed in metastatic thyroid carcinomas and non-metastatic thyroid carcinomas.
The thyroid is an endocrine gland involved in the homeostatic regulation of bodily functions. Its basic morphologic unit is the follicle, which contains two major parenchymal cell types: the follicular cells and the parafollicular cells.
The diseases affecting the thyroid gland can be classified as benign and malignant. Benign diseases can include diffuse goiter, such as Graves"" disease, and nodular goiter, such as nodular hyperplastic goiter. Other benign thyroid disorders include thyroiditis and benign neoplasms, such as adenomas.
Thyroid cancer is a common endocrine tumor. The reported incidence of thyroid cancer is about 4 per 100,000, with the number of afflicted males and females occurring at a relative ratio of 2:1. It is possible that the actual incidence of thyroid cancer is higher, as thyroid cancers, like prostate malignancies, are most typically found as occult tumors during autopsy.
Thyroid cancers are typically classified according to their cellular origin and level of differentiation. For example, follicular cells produce well-differentiated carcinomas and anaplastic carcinomas, while parafollicular cells produce medullary thyroid carcinomas. Other cancers associated with the thyroid gland include sarcomas, originating from stromal cells of the thyroid, and lymphomas, which originate from immune cells associated with the thyroid
A majority of thyroid malignancies are well-differentiated, slow-growing, and remain local to the thyroid gland. Removal of the thyroid, followed by 125I gamma irradiation of any remaining thyroid tissue, typically elicits a good response and prognosis for patients whose cancer has not spread beyond the thyroid gland. Extension of tumors into adjacent neck structures or more distant sites from the thyroid is associated with a significantly worse prognosis. The prognostic significance of local metastases to lymph nodes in the region of the lymph node is less clear.
The mechanisms by which thyroid cancers metastasize to distant sites in the body are not completely understood. For example, not all the genes whose expression levels change in response to a thyroid metastasis have been identified. In addition to providing potential targets in metastatic tissue that could be used for treat metastasized genes, such genes could also be used to diagnose metastatic tissues.
The invention is based in part on the discovery of genes whose expression levels can be correlated to one or more metastatic cancerous states in a thyroid cell. Measuring expression levels of these genes in a sample cell population allows for the type and tumor stage of the cells in the sample to be determined.
Accordingly, in one aspect the invention relates to genes that are differentially expressed in metastatic versus non-metastatic thyroid cancer. These differentially expressed genes are collectively referred to herein as xe2x80x9cMetastatic Thyroid Cancerxe2x80x9d genes (xe2x80x9cMTC genesxe2x80x9d). The corresponding gene products are referred to as xe2x80x9cMTC productsxe2x80x9d and/or xe2x80x9cMTC proteinsxe2x80x9d. The MTC genes include E-cadherin, alpha-1-antitrypsin, manganese superoxide dismutase, thyroglobulin, fibronectin, CD18, calpain, clusterin, cathepsin E, cystatin B, RIG-E, p8=candidate of metastasis 1, periplakin, neuropilin, proteasome subunit HC5, NET-1, ras GTPase-activating-like protein (IQGAP1), DUSP6 dual specificity MAP kinase phosphatase, SET binding factor (SBF), 5-lipoxygenase, lipocortin I, lipocortin II, annexin II, calgizzarin, spernmidine/spermine N1-acetyltransferase (SSAT), daunorubicin-binding protein=aldehyde dehydrogenase 2, gelsolin, integrin alpha-3, Type IV collagenase, antileukoprotease, STE20-like protein kinase 3 (STK3), peflin, and kinectin.
In various aspects, the invention includes methods of categorizing thyroid neoplasms, diagnosing thyroid carcinomas, assessing the efficacy of a treatment of a thyroid carcinoma in a subject, and assessing the prognosis of a subject with a thyroid carcinoma. Each of these methods involves providing a test cell population from a subject capable of expressing one or more metastatic thyroid carcinoma nucleic acid sequences, termed MTC sequences, measuring the expression of these MTC sequences in the test cell population, and comparing the levels of expression in the test cell population with the expression levels in a reference cell population whose thyroid carcinoma stage is known.
In a further aspect, the invention includes a method of selecting an individualized therapeutic agent appropriate for a particular subject. This method includes providing from the subject, a test cell population comprising a cell capable of expressing one or more MTC sequences, contacting the test cell population with the therapeutic agent, and comparing the expression of the MTC sequences in the test cell population to the expression levels in a reference cell population whose thyroid carcinoma stage is known.
In another aspect, the invention provides a method of identifying a candidate therapeutic agent for treating thyroid carcinomas. This method includes providing a test cell population capable of expressing one or more MTC sequences, contacting the test cell population with a candidate therapeutic agent, and comparing the expression of the MTC sequences to the expression in a reference cell population whose thyroid carcinoma stage is known.
The invention further provides a method of treating metastatic cancer. In one embodiment, this method includes administering to a patient suffering from or at risk for developing metastatic cancer, an agent that increases the expression of one or more MTC sequences that are down-regulated in metastatic versus non-metastatic cancer. In another embodiment, this method involves administering an agent that decreases the expression of one or more MTC sequences that are up-regulated in metastatic versus non-metastatic cancer.
Further provided is a kit comprising one or more reagents for detecting the presence of two or more MTC nucleic acid sequences and an array of probe nucleic acids capable of detecting two or more MTC nucleic acid sequences. Also provided are isolated nucleic acid molecules that are differentially expressed in metastatic vs. non-metastatic thyroid cancer, as well as single nucleotide polymorphisms in MTC sequences, and methods of using the MTC single nucleotide polymorphisms.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description and from the claims.